In pursuit of an inhibitory drug for the proton channel

Pupo, Amaury; León, Carlos Gonzalez

doi:10.1073/pnas.1408808111

Cited by 9 publications

(13 citation statements)

References 23 publications

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“…Two major strategies have proved successful in developing ligands targeting the Hv1 VSD: one focused on the use of peptide toxins binding the channel extracellular side ( Alabi et al, 2007 ; Tang et al, 2020 ; Zhao et al, 2018 ) and the other focused on small organic molecules targeting the channel intracellular side ( Hong et al, 2014 ; Hong et al, 2013 ; Kalia and Swartz, 2013 ; Pupo and Gonzalez León, 2014 ). Some of these ligands have found applications as pharmacological tools to study the gating and permeation mechanisms of proton-conducting VSDs ( Chamberlin et al, 2014 ; Gianti et al, 2016 ; Hong et al, 2015 ; Qiu et al, 2013 ; Wobig et al, 2020 ) and the role of Hv1-mediated proton currents in cellular physiology ( Asuaje et al, 2017 ; Mészáros et al, 2020 ; Rennhack et al, 2017 ; Zhao et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD–ligand interactions

Zhao

Luan

Galpin

et al. 2021

Journal of General Physiology

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The human voltage-gated proton channel Hv1 is a drug target for cancer, ischemic stroke, and neuroinflammation. It resides on the plasma membrane and endocytic compartments of a variety of cell types, where it mediates outward proton movement and regulates the activity of NOX enzymes. Its voltage-sensing domain (VSD) contains a gated and proton-selective conduction pathway, which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). Mutation of Hv1 residue F150 to alanine (F150A) was previously found to increase 2GBI apparent binding affinity more than two orders of magnitude. Here, we explore the contribution of aromatic interactions between the inhibitor and the channel in the presence and absence of the F150A mutation, using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated phenylalanines via nonsense suppression methodology. Our data suggest that the increase in apparent binding affinity is due to a rearrangement of the binding site allowed by the smaller residue at position 150. We used this information to design new arginine mimics with improved affinity for the nonrearranged binding site of the wild-type channel. The new compounds, named “Hv1 Inhibitor Flexibles” (HIFs), consist of two “prongs,” an aminoimidazole ring, and an aromatic group connected by extended flexible linkers. Some HIF compounds display inhibitory properties that are superior to those of 2GBI, thus providing a promising scaffold for further development of high-affinity Hv1 inhibitors.

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Section: Introductionmentioning

confidence: 99%

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD–ligand interactions

Zhao

Luan

Galpin

et al. 2021

Journal of General Physiology

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“…Because of its roles in human health and disease (De-Coursey, 2013;Pupo and Gonzalez León, 2014;Seredenina et al, 2015), Hv1 is an emerging drug target for cancer and stroke. The channel is found in cellular compartments that experience strong mechanical forces, such as the apical membrane of airway epithelial cells (Iovannisci et al, 2010), where motile cilia beat in coordinated waves, and the flagellar tail of sperm cells (Lishko et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Hv1 proton channel responds to mechanical stimuli

Pathak

Tran

Luan

et al. 2016

Journal of General Physiology

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“…A modified version of 2GBI (CIGBI) that makes it more permeable to the cell membrane was later identified to bind Hv1 more efficiently, making a step forward to the development of pharmacological treatments for diseases caused by Hv1 hyperactivity (Hong et al, 2014). Nonetheless, the relative low potency and uncertainty about specificity against Hv1 remains a problem (Pupo and Gonzalez Leon, 2014).…”

Section: Proton Channel Blockersmentioning

confidence: 99%

Functions and Mechanisms of the Voltage-Gated Proton Channel Hv1 in Brain and Spinal Cord Injury

Ritzel

2021

Front. Cell. Neurosci.

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The voltage-gated proton channel Hv1 is a newly discovered ion channel that is highly conserved among species. It is known that Hv1 is not only expressed in peripheral immune cells but also one of the major ion channels expressed in tissue-resident microglia of the central nervous systems (CNS). One key role for Hv1 is its interaction with NADPH oxidase 2 (NOX2) to regulate reactive oxygen species (ROS) and cytosolic pH. Emerging data suggest that excessive ROS production increases and requires proton currents through Hv1 in the injured CNS, and manipulations that ablate Hv1 expression or induce loss of function may provide neuroprotection in CNS injury models including stroke, traumatic brain injury, and spinal cord injury. Recent data demonstrating microglial Hv1-mediated signaling in the pathophysiology of the CNS injury further supports the idea that Hv1 channel may function as a key mechanism in posttraumatic neuroinflammation and neurodegeneration. In this review, we summarize the main findings of Hv1, including its expression pattern, cellular mechanism, role in aging, and animal models of CNS injury and disease pathology. We also discuss the potential of Hv1 as a therapeutic target for CNS injury.

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In pursuit of an inhibitory drug for the proton channel

Cited by 9 publications

References 23 publications

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD–ligand interactions

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD–ligand interactions

The Hv1 proton channel responds to mechanical stimuli

Functions and Mechanisms of the Voltage-Gated Proton Channel Hv1 in Brain and Spinal Cord Injury

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